Submissions for variant NM_001360.3(DHCR7):c.461C>G (p.Thr154Arg)

gnomAD frequency: 0.00003  dbSNP: rs143312232

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790776	SCV000231620	likely pathogenic	not provided	2017-01-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002312988	SCV000848918	pathogenic	Inborn genetic diseases	2021-07-13	criteria provided, single submitter	clinical testing	The c.461C>G (p.T154R) alteration is located in exon 6 (coding exon 4) of the DHCR7 gene. This alteration results from a C to G substitution at nucleotide position 461, causing the threonine (T) at amino acid position 154 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD) database, the DHCR7 c.461C>G alteration was observed in 0.01% (25/281248) of total alleles studied, with a frequency of 0.02% (22/127708) in the European (non-Finnish) subpopulation. This mutation has been detected in four individuals with Smith-Lemli-Opitz syndrome (SLOS); three of the individuals carried another pathogenic mutation although the phase of these alterations was unknown (Witsch-Baumgartner, 2001; Correa-Cerro, 2005; Scalco, 2005; Haas, 2007). Based on our internal structural analysis, this mutation is predicted to be more destabilizing than nearby known pathogenic variants (Li, 2015). The p.T154R alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV000179381	SCV000915553	likely pathogenic	Smith-Lemli-Opitz syndrome	2018-08-16	criteria provided, single submitter	clinical testing	The DHCR7 c.461C>G (p.Thr154Arg) missense variant has been reported in at least four studies in which it is found in a total of four patients with either diagnosed or suspected Smith-Lemli-Opitz syndrome. The variant was present in three patients in a compound heterozygous state and in one patient in a heterozygous state, in whom it is not clear if a second variant was present (Witsch-Baumgartner et al. 2001; Correa-Cerro et al. 2005; Scalco et al. 2005; Haas et al. 2007). The p.Thr154Arg variant was also identified in a heterozygous state in six unaffected individuals in a large cohort undergoing routine carrier screening using next generation sequencing (Lazarin et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Thr154Arg variant is classified as likely pathogenic for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000179381	SCV000953377	pathogenic	Smith-Lemli-Opitz syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 154 of the DHCR7 protein (p.Thr154Arg). This variant is present in population databases (rs143312232, gnomAD 0.02%). This missense change has been observed in individual(s) with DHCR7-related conditions (PMID: 15805162, 15952211, 17237122, 20694756). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 166988). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DHCR7 protein function with a positive predictive value of 95%. This variant disrupts the p.Thr154 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10677299, 10995508, 11427181, 15896653, 18249054, 22391996). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000179381	SCV001163336	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000179381	SCV001554625	pathogenic	Smith-Lemli-Opitz syndrome	2021-03-26	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.461C>G (p.Thr154Arg) results in a non-conservative amino acid change located in the membrane-associated helix (MAH 3, Waterham_2012) of the encoded protein sequence . Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 774648 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (4e-05 vs 0.0043), allowing no conclusion about variant significance. c.461C>G has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner_2001, Correa-Cerro__2005, Scalco_2005, Haas_2007, Boland_2016). These data indicate that the variant is very likely to be associated with disease. Additionally, another variant at the same residue T154M has been observed in affected SLOS individuals (Witsch-Baumgartner_2001, Correa-Cerro__2005, Boland_2016), suggesting that the variant is clinically significant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2) and likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000179381	SCV001752454	likely pathogenic	Smith-Lemli-Opitz syndrome	2021-07-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000790776	SCV001803604	pathogenic	not provided	2022-07-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20694756, 10995508, 10677299, 29300326, 28166604, 23042628, 15805162, 11175299, 11241839, 15670717, 12914579, 17237122, 15952211, 34426522)
Revvity Omics, Revvity	RCV000179381	SCV002024078	likely pathogenic	Smith-Lemli-Opitz syndrome	2021-04-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000179381	SCV003799979	pathogenic	Smith-Lemli-Opitz syndrome	2022-10-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917496	SCV004732253	pathogenic	DHCR7-related disorder	2023-12-13	criteria provided, single submitter	clinical testing	The DHCR7 c.461C>G variant is predicted to result in the amino acid substitution p.Thr154Arg. This variant has been reported in at least three patients with Smith-Lemli-Opitz syndrome (SLOS) in addition to a second known pathogenic DHCR7 variant (Correa-Cerro et al. 2005. PubMed ID: 15805162; Scalco et al. 2005. PubMed ID: 15952211; Haas et al. 2007. PubMed ID: 17237122). It has also been reported in other SLOS patient cohorts without additional genetic segregation data included about the reported patients (Witsch-Baumgartner et al. 2001. PubMed ID: 11241839; Witsch-Baumgartner et al. 2001. PubMed ID: 11175299). A different substitution of the same amino acid (p.Thr154Met) has been reported in a number of compound heterozygous SLOS patients (Wassif et al. 2005. PubMed ID: 15896653; Jezela-Stanek et al. 2008. PubMed ID: 18249054; Roullet et al. 2012. PubMed ID: 22391996) and in an expression study using HEK293 cells, the p.Thr154Met substitution was found to lead to <5% expression (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299). The p.Thr154 amino acid is located in the third membrane-associated helix (MAH 3) of the DHCR7 protein (Waterham and Hennekam. 2012. PubMed ID: 23042628), and an internal summary of amino acid substitution prediction programs predicts the p.Thr154Arg change to be “damaging” (Liu et al. 2016. PMID: 26555599). This variant has been reported at a frequency of ~0.015% in individuals of European (Non-Finnish) origin in a large population database and has been interpreted in ClinVar as pathogenic/likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/166988/). This variant is interpreted as pathogenic.
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000179381	SCV000536765	likely pathogenic	Smith-Lemli-Opitz syndrome	2016-04-27	no assertion criteria provided	research
Counsyl	RCV000179381	SCV000678157	likely pathogenic	Smith-Lemli-Opitz syndrome	2017-02-24	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000179381	SCV002093050	pathogenic	Smith-Lemli-Opitz syndrome	2020-10-12	no assertion criteria provided	clinical testing